In 2016, 63 632 persons died of a drug overdose in the United States; 66.4% (42 249) involved an opioid.1 Opioid-involved deaths include prescription opioid analgesics (e.g., morphine, oxycodone), illicit opioids (e.g., heroin, illicitly manufactured fentanyl [IMF]), or both. Although prescription and illicit opioid overdoses are closely entwined,2 it is important to differentiate the deaths to craft appropriate prevention and response efforts. Unfortunately, disentangling these deaths is challenging because multiple drugs are often involved. Additionally, death certificate data do not specify whether the drugs were pharmaceutically manufactured and prescribed by a health care provider, pharmaceutically manufactured but not prescribed to the person (i.e., diverted prescriptions), or illicitly manufactured.
THE CHANGING OPIOID OVERDOSE EPIDEMIC
The United States has seen rapid changes in the illicit opioid supply. Availability of illicitly manufactured synthetic opioids (e.g., fentanyl) that traditionally were prescription medications has increased. This has blurred the lines between prescription and illicit opioid-involved deaths. In one study in 27 states, Gladden et al.3 examined data on drug products obtained by law enforcement that tested positive for fentanyl (fentanyl submissions) and deaths involving synthetic opioids other than methadone (referred to as synthetic opioids). From 2013 to 2014, fentanyl submissions increased by 426%. The increases were strongly correlated with increases in synthetic opioid deaths but not with pharmaceutical fentanyl prescribing rates, suggesting that the increases were largely due to IMF.3 In a recent report, fentanyl was detected in at least half of the opioid overdose deaths from July to December 2016 in 7 of the 10 states examined.4
Traditionally, the Centers for Disease Control and Prevention (CDC) and others have included synthetic opioid deaths in estimates of “prescription” opioid deaths. However, with IMF likely being involved more recently, estimating prescription opioid–involved deaths with the inclusion of synthetic opioid–involved deaths could significantly inflate estimates.
MORE CONSERVATIVE ESTIMATION APPROACH
A new, more conservative estimation of prescription opioid–involved deaths is proposed to better differentiate deaths involving prescription (pharmaceutically manufactured) opioids from deaths involving illicit opioids (heroin, IMF). Pharmaceutically manufactured opioids are considered prescription opioids for estimation purposes because most persons misusing them reported obtaining them in a way that originated with a prescription (misusing own prescription or obtaining from friends or relatives). Only 4.9% bought opioids from a drug dealer or stranger, and 5.6% reported obtaining them by stealing from a doctor’s office, clinic, hospital, or pharmacy or in some other way.5
The National Vital Statistics System (NVSS) multiple cause-of-death mortality files record drug overdose deaths, which are identified with the International Classification of Diseases, 10th Revision (ICD-10; Geneva, Switzerland: World Health Organization; 1992), according to the underlying cause-of-death codes X40 to X44 (unintentional), X60 to X64 (suicide), X85 (homicide), or Y10 to Y14 (undetermined intent). Among deaths with drug overdose as the underlying cause, the type of opioid is indicated by the following ICD-10 multiple cause-of-death codes: opium (T40.0); heroin (T40.1); natural and semisynthetic opioids (T40.2); methadone (T40.3); synthetic opioids other than methadone (T40.4); and other and unspecified narcotics (T40.6).
Under the CDC’s traditional method of calculating prescription opioid overdose deaths with NVSS, deaths involving natural and semisynthetic opioids and synthetic opioids as well as methadone are included. Under a more conservative method, deaths involving only natural and semisynthetic opioids and methadone are included. Deaths involving synthetic opioids are removed and calculated separately because of the high proportion of deaths that likely involve IMF.
With the traditional method, an estimated 32 445 prescription opioid–involved deaths occurred in 2016. With the more conservative method, 17 087 prescription opioid–involved deaths occurred in 2016 (Table 1). Longitudinal trends indicated a rapid increase in death rates involving synthetic opioids from 2013 to 2016 (annual percent change = 87.7%), whereas death rates involving natural and semisynthetic opioids remained relatively stable from 2009 to 2016 (annual percent change = 3.4%).1 Death rates involving methadone have significantly decreased since 2006 (annual percent change = 6.2%).1 Thus, rates of prescription opioid–involved deaths estimated with the traditional method may have been inflated in recent years because of the increase in death rates involving synthetic opioids (e.g., fentanyl).
Limitations of the more conservative method include underestimating prescription opioid–involved deaths because it excludes prescription synthetic opioid deaths (e.g., fentanyl patch, tramadol). The number of prescription opioid–involved deaths that included diverted prescriptions or those that were counterfeit and imported illegally from other countries remains unknown. Toxicology testing cannot distinguish between pharmaceutical fentanyl and IMF3; therefore, all deaths involving synthetic opioids are removed in the conservative method and reported as their own category. Furthermore, drugs are not specified on the death certificate in approximately 20% of overdose deaths, which leads to an underestimation of opioid-involved deaths.1 Finally, in 2014, multiple drugs were involved in almost half of the drug overdose deaths that mentioned at least one specific drug on the death certificate (36 667 deaths).2 Therefore, opioids may not have been the only drug involved, or multiple opioids may have been involved.
CONCLUSIONS Although the new approach is more conservative, this estimate may better represent prescription opioid–involved deaths because deaths likely involving IMF are excluded. Opioid-involved deaths were at their greatest levels ever in 2016. Prescription opioid–involved deaths estimated more conservatively have leveled off since 2012. However, the traditional measure has shown sharp increases from 2014 through 2016, paralleling increases in synthetic opioid deaths. Death rates under both measures remain alarmingly high. Because of the increasing evidence that deaths involving synthetic opioids are likely a result of IMF, this more conservative approach likely provides a relatively more accurate number of prescription opioid–involved deaths, even though it excludes synthetic opioids that may have been pharmaceutically manufactured and prescribed. The traditional approach to NVSS analysis does not adequately reflect the changing landscape of the opioid overdose epidemic, which has become increasingly worse because of illicit opioids. Advances in surveillance, such as the CDC National Center for Injury Prevention and Control’s State Unintentional Drug Overdose Reporting System, which currently funds 32 states and Washington, DC, allow for data abstraction from preliminary death certificates and medical examiner or coroner reports on unintentional and undetermined opioid overdose deaths, with detailed data from death scene investigations and toxicology testing. With expanded surveillance improvements, CDC can disentangle prescription and illicit opioid-involved deaths more effectively, with specific drug types, such as IMF, identified.4
Obtaining an accurate count of the true burden and differentiating between prescription and illicit opioid-involved deaths are essential to implement and evaluate public health and public safety efforts. Distinct prevention strategies are required. In addition, if deaths involving synthetic opioids—likely IMF—are categorized as prescription opioid overdose deaths, then the ability to evaluate the effect of interventions targeting high-risk prescribing practices (e.g., guidelines, prescription drug monitoring programs) on prescription opioid–involved deaths is hindered. Decreases in prescription opioid–involved deaths could be masked by increases in IMF deaths, resulting in inaccurate conclusions. Strategies to prevent prescription opioid misuse and overdose may include academic detailing on the CDC “Guideline for Prescribing Opioids for Chronic Pain”6 and improving prescription drug monitoring program use. These interventions also could potentially reduce illicit opioid use and overdose long term. However, in areas experiencing an influx of IMF, increasing access to naloxone, educating emergency responders about higher dosage requirements, and enhancing law enforcement strategies to remove illicit drugs could have effects. Increasing linkages to risk reduction programs and medication-assisted treatment also is critical for persons with opioid use disorder.7 Finally, enhanced toxicology testing, reporting of the specific drugs involved in deaths, and law enforcement strategies that target illicit drug diversion and availability are important complements. Ultimately, urgent work remains to end the opioid overdose epidemic. A collaborative approach between public health, clinical medicine, and law enforcement holds the greatest promise.
ACKNOWLEDGMENTS We thank Michele Bohm, MPH, and Deborah Dowell, MD, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, Centers for Disease Control and Prevention. REFERENCES 1. Hedegaard H, Warner M, Miniño AM. Drug Overdose Deaths in the United States, 1999–2016. Hyattsville, MD: National Center for Health Statistics; 2017. NCHS Data Brief, No. 294. [Google Scholar] 2. Warner M, Trinidad JP, Bastian BA, Minino AM, Hedegaard H. Drugs most frequently involved in drug overdose deaths: United States, 2010-2014. Natl Vital Stat Rep. 2016;65(10):1–15. [PubMed] [Google Scholar] 3. Gladden RM, Martinez P, Seth P. Fentanyl law enforcement submissions and increases in synthetic opioid-involved overdose deaths - 27 states, 2013-2014. MMWR Morb Mortal Wkly Rep. 2016;65(33):837–843. [PubMed] [Google Scholar] 4. O’Donnell JK, Halpin J, Mattson CL, Goldberger BA, Gladden RM. Deaths involving fentanyl, fentanyl analogs, and U-47700-10 states, July-December 2016. MMWR Morb Mortal Wkly Rep. 2017;66(43):1197–1202. [PMC free article] [PubMed] [Google Scholar] 5. Hughes A, Williams MR, Lipari RN, Bose J, Copello EAP, Kroutil LA. Prescription Drug Use and Misuse in the United States: Results From the 2015 National Survey on Drug Use and Health. 2016. NSDUH Data Review. Available at: https://www.samhsa.gov/data/sites/default/files/NSDUH-FFR2-2015/NSDUH-FFR2-2015.htm. Accessed November 2, 2017. 6. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016. MMWR Recomm Rep. 2016;65(1):1–49. [PubMed] [Google Scholar] 7. Frank RG, Pollack HA. Addressing the fentanyl threat to public health. N Engl J Med. 2017;376(7):605–607. [PubMed] [Google Scholar]
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